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      Boosting the MHC Class II-Restricted Tumor Antigen Presentation to CD4+ T Helper Cells: A Critical Issue for Triggering Protective Immunity and Re-Orienting the Tumor Microenvironment Toward an Anti-Tumor State

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          Abstract

          Although the existence of an immune response against tumor cells is well documented, the fact that tumors take off in cancer patients indicates that neoplastic cells can circumvent this response. Over the years many investigators have described strategies to rescue the anti-tumor immune response with the aim of creating specific and long-lasting protection against the disease. When exported to human clinical settings, these strategies have revealed in most cases a very limited, if any, positive outcome. We believe that the failure is mostly due to the inadequate triggering of the CD4+ T helper (TH) cell arm of the adaptive immunity, as TH cells are necessary to trigger all the immune effector mechanisms required to eliminate tumor cells. In this review, we focus on novel strategies that by stimulating MHC class II-restricted activation of TH cells generate a specific and persistent adaptive immunity against the tumor. This point is of critical importance for both preventive and therapeutic anti-tumor vaccination protocols, because adaptive immunity with its capacity to produce specific, long-lasting protection and memory responses is indeed the final goal of vaccination. We will discuss data from our as well as other laboratories which strongly suggest that triggering a specific and persistent anti-tumor CD4+ TH cell response stably modify not only the tumor microenvironment but also tumor-dependent extratumor microenvironments by eliminating and/or reducing the blood-derived tumor infiltrating cells that may have a pro-tumor growth function such as regulatory CD4+/CD25+ T cells and myeloid-derived-suppressor cells. Within this frame, therefore, we believe that the establishment of a pro-tumor environment is not the cause but simply the consequence of the tumor strategy to primarily counteract components of the adaptive cellular immunity, particularly TH lymphocytes.

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          Cancer immunotherapy: moving beyond current vaccines.

          Great progress has been made in the field of tumor immunology in the past decade, but optimism about the clinical application of currently available cancer vaccine approaches is based more on surrogate endpoints than on clinical tumor regression. In our cancer vaccine trials of 440 patients, the objective response rate was low (2.6%), and comparable to the results obtained by others. We consider here results in cancer vaccine trials and highlight alternate strategies that mediate cancer regression in preclinical and clinical models.
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            Taking dendritic cells into medicine.

            Dendritic cells (DCs) orchestrate a repertoire of immune responses that bring about resistance to infection and silencing or tolerance to self. In the settings of infection and cancer, microbes and tumours can exploit DCs to evade immunity, but DCs also can generate resistance, a capacity that is readily enhanced with DC-targeted vaccines. During allergy, autoimmunity and transplant rejection, DCs instigate unwanted responses that cause disease, but, again, DCs can be harnessed to silence these conditions with novel therapies. Here we present some medical implications of DC biology that account for illness and provide opportunities for prevention and therapy.
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              Dendritic-cell-based therapeutic cancer vaccines.

              The past decade has seen tremendous developments in novel cancer therapies through the targeting of tumor-cell-intrinsic pathways whose activity is linked to genetic alterations and the targeting of tumor-cell-extrinsic factors, such as growth factors. Furthermore, immunotherapies are entering the clinic at an unprecedented speed after the demonstration that T cells can efficiently reject tumors and that their antitumor activity can be enhanced with antibodies against immune-regulatory molecules (checkpoint blockade). Current immunotherapy strategies include monoclonal antibodies against tumor cells or immune-regulatory molecules, cell-based therapies such as adoptive transfer of ex-vivo-activated T cells and natural killer cells, and cancer vaccines. Herein, we discuss the immunological basis for therapeutic cancer vaccines and how the current understanding of dendritic cell and T cell biology might enable the development of next-generation curative therapies for individuals with cancer. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                18 January 2014
                18 February 2014
                2014
                : 4
                : 32
                Affiliations
                [1] 1Department of Surgical and Morphological Sciences, University of Insubria , Varese, Italy
                Author notes

                Edited by: Jozsef Dudas, Medical University Innsbruck, Austria

                Reviewed by: Jozsef Dudas, Medical University Innsbruck, Austria; Sieghart Sopper, Medical University Innsbruck, Austria

                *Correspondence: Roberto S. Accolla, Laboratory of General Pathology and Immunology, Department of Surgical and Morphological Sciences, University of Insubria, Via Ottorino Rossi 9, Varese 21100, Italy e-mail: roberto.accolla@ 123456uninsubria.it ; accolla.roberto@ 123456gmail.com

                This article was submitted to Molecular and Cellular Oncology, a section of the journal Frontiers in Oncology.

                Article
                10.3389/fonc.2014.00032
                3927100
                24600588
                6a94765e-4e62-4f45-8a91-ca6970e60c87
                Copyright © 2014 Accolla, Lombardo, Abdallah, Raval, Forlani and Tosi.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 20 December 2013
                : 04 February 2014
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 73, Pages: 9, Words: 8026
                Categories
                Oncology
                Review Article

                Oncology & Radiotherapy
                ciita,mhc class ii,t helper cells,tumor vaccines,anti-tumor immunity
                Oncology & Radiotherapy
                ciita, mhc class ii, t helper cells, tumor vaccines, anti-tumor immunity

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